Mechanisms Of Of Resistance Resistance To BRAF/MEK BRAF .
Mechanisms of Resistance toBRAF/MEK InhibitorsHow to overcome themMaria González CaoIOR. Institut Universitari Dexeus. BarcelonaJune 2016GEM
Summary1.2.PathwayDifferent responders1. Long responders (15-20%): CR-----------------------------------BRAFi MEKi2.Refractary patiens (5-10%): Intrinsic resistance---- Immunotherapy, novel drugs3.Resistance (80%): adaptative and acquired3.1. Heterogeneity: ----------------------Targeted drugs at progression: cfDNA,Novel combinations 1st lineNovel drugs3.2. Adaptative resistance-----------------------On/off schedule
Main pathways in BRAF mutant melanomaKarachaliou et al. ATM 2016
1. Long term survival Dabra TrameLong et al, JCO. Jan, 2016. DOI: 10.1200/JCO.2015.62.9345
PFS and OS by Best ResponseProgression-Free 40.80.668%0.0PFS Probability90%1-yr0.2CRPRSDPDNEOS Probability2-yr1.01-yrOverall Survival0128715124003350200036MonthsNo. at riskComplete Response (CR) 100Partial Response (PR)316Stable Disease (SD)150Progressive Disease (PD) 35Not Evaluable (NE)162412No. at risk55000Complete ResponsePartial ResponseStable DiseaseProgressive DiseaseNot 15114005PRESENTED BY GV LONG AT SMR 2015
Five Baseline Factors Influenced OSN 617LDH NormalLDH ULNN 3981Y 85%2Y 67%3Y 57%Disease Sites 3Disease Sites 3N 2371Y 90%2Y 75%3Y 70%N 1611Y 76%2Y 55%3Y 38%N 2191Y 54%2Y 25%3Y 7%LDH 1- 2 ULNLDH 2 ULNN 1491Y 60%2Y 33%3Y 9%ECOG N 093aRegression tree analysis.1Y 71%2Y 43%3Y NEN 701Y 40%2Y 7%3Y 7%ECOG 1N 561Y 42%2Y 19%3Y 16%NE, not estimable.PRESENTED BY GV LONG AT SMR 2015
Long survivors with BRAFi: only BRAF mutations on WESWheler. BMC Cancer 2015
Bone BiopsyH-EHMB45S-100Dooley et al. Targ Oncol 2016Autopsy: colitis perforationGonzalez-Cao, BoadaA et al. Oncotarget In press
2. BRAFi Resistant Mechanisms: intrinsic resistance%Primary/acquirTreatmentNRAS mut15P/AMek simvastatin, Meki CDK4i, MEKi EGFRi, MEKi abt263, smvastatin flavopiridol,simvastatin CDK4i, MEKi PI3KiPLX7904, ERKiMEKi nefinavirBRAF FUSION2PMEKiMEK mut (NO P162S)15A/PERKI (SCH7729 MERK)NF2A/PMEKi MTORi, CRAFi BRAFi, panRAFi (AZ628), ERKiCOT sobre?A/P-RAC13/14PPAKiMELP12410/134PMEKi, ERKiEGFR, pdgfr6/16A/PDasatinib, AKTi EGFRi, (¡?), braf pi3kiHolidays, HSP90iHGF?PBRAFi METi, BRAFi AKTiPTEN loss, or RB inact10-30P/ABRAFi everolimuBRAFi PI3KiERB2, ERB3?A/PBRAFi Lapa ¿?MED12?Mediator ABRAFi TGFBi (YR-290)BCL2A1-MITF?A(PR to ERKi, BRAFi, MEKi; S BRAFi bcla2i, obatoclax; Antiretroviral drugs
PTEN deletion/mutant pretreatment in BRAFiHartsough J Invest Dermatol 2013, Shi CCR 2013
Percentage Progression FreeAddition of Cobimetinib to Vemurafenib Overcomes theNegative Impact of PTEN Loss on PFSVem PTEN (N 82)Vem PTEN loss (N 32)Vem cobi PTEN (N 92)Vem cobi PTEN loss (N 32)100806040200.00PTEN : H score 50PTEN loss: H score 50McArthur. ECCO 2015200400Days600800HR 0.36 (95% CI, 0.19-0.65)For PTEN loss Vem Cobi vs. Vem
Gentry. Cancer Cell 2013
TORC1 suppression increases the apoptotic response inBRAF-mutant melanomasAZD8055 (mTORC inhibitor), GDC0941 (pan-PI3K inhibitor), BEZ235 (dual PI3K-TORC inhibitor), ABT-263 (BH3 mimetic)P-S6 measurement can effectively identify tumors with ERK-independent resistance.Combinations of RAF inhibitor with a TORC inhibitor, a PI3K inhibitor, or a BH3 mimetic,may be effective.Back up informationCorcoran et al. STM 2013
Clinical trials using mTOR H3 mimeticNºCompletedcombinationOngoingNCT0189585
NF1 critically regulates KRAS and HRAS in melanomasMaertens O et al. Cancer Discovery 2013;3:338-349
NF1 was mutated in 38.7% of non BRAF/NRAS melanomas(29/75) and in 70% of non BRAF/NRAS samples with a UVsignatureCGAN. Cell 2015
NF1 loss16/121 melanomas harbored a NF1 missense or nonsense mutationBut clinically resistance has been only demonstrated in one patient that hadit in the initial byopsy and had a short PFSSensitive to pan-RAF inhibitor AZ628, the ERK inhibitor VTX11e,and the combination of a MEK mTOR inhibitor (PD0325901 and rapamycin)Gibney G T , Cancer Discovery 2013; Maertena, Cancer Discov 2013
Whole-exome sequencing identifies NF1 mutations in tumors of melanomapatients exhibiting resistance to vemurafenibWhittaker S R et al. Cancer Discovery 2013;3:350-362
NF1 melanoma: growth responses to selumetinib and ERKiSCH772984Krauthammer. Nat Genetics 2015
Clinical trialsDrugMecCombinationStatusNºLXH254 ompletedwithoutpublishedresults
Stroma1Zhang et al. Sci Signal12014
Lin et al. Nat Genet 2015
β-catenin-LEF1 and YAP1 signaling antagonistically co-regulate the tumorcell-intrinsic, apoptotic threshold of melanoma to MAPKi.Hugo Cell 2015
Lin et al. Nat Genet 2015
HGF from stromal cells: poor response Stromal cell linessecrete HGF in co-culturewith BRAFmut cell lines Innate resistance BRAFi METiStraussman Nature 2012
Clinical trialsDrugMecCombinationStatusNºINC280 (Nov)cMETiBRAFi/MEKiOngoingLogic2
Macrophage derived TNF: MITF upregulationMITF target BCL2A1 has been shown toantagonize BRAF inhibitionSmith et al. Cancer Discov 2014
Acquired MITF amplification:resistance to BRAFi, MEKi and ERKiVan Allen E M et al. Cancer Discovery 2014;4:94-109
AmplificationsCGAN. Cell 2015
Drug repositioning identifies nelfinavir mesylate as asuppressor of MITF expressionPAX3-mediatedoverexpression of MITF as a reversibleresistance mechanism to MAPK-pathwaySmith . Cancer Cell 2016
Intrinsically resistant cells showed diminished MITF expression and MITFtranscriptional activity (as measured by levels of MITF target genes TYRP1 ,MLANA , and PMEL ; 4/4 lines) and increase of AXL expression (2/4 lines).Intrinsic resistance is not simply related to AXL expression.Konieczkowski et al. Cancer Discov 2014
Low MITF/AXL ratio predict early resistance to ERK inhibition MITF low/AXL high is common in BRAF and NRAS melanomas MITF low in naive melanoma predict high resistance Also Mitf low in some melanomas with adquired resistance: they must be treated with AXLi combined with MAPKiMullerl et al. Nat Commun 2014Konieczkowski et al. Cancer Discov 2014
Clinical nicalcabozantinibAXLi-No trials mpletedwithout LipreclinicalMGCD265MGCD516AXLipreclinicalNº
Clinical sensRT/TMZOngoingGBM/NSCLCNº
3. Acquired resistanceShi H. Cancer Discovery 2013 Nov
3. Acquired resistance%Primary/acquirTreatmentNRAS mut15P/AMek simvastatin, Meki CDK4i, MEKi EGFRi, MEKi abt263,smvastatin flavopiridol, simvastatin CDK4i, MEKi PI3KiPLX7904, ERKiBraf ampl15ABRAFi intemitente , Dosis de braf mayor, ERKiSplicing20AERKi BRAFi, drug holidays, higher doses of BRAFi or MEKi, PLX7004MEK mut (NO P162S)15A/PERKI (SCH7729 MERK)NF2A/PMEKi MTORi, CRAFi BRAFi, panRAFi (AZ628), ERKiCOT sobre?A/P-IGFR,4/11AMEKi IGFRi, BRAFi IGFRi, MEKi AKTi or mtori or pi3ki, HSP90iEGFR, pdgfr6/16A/PDasatinib, AKTi EGFRi, (¡?), braf pi3kiHolidays, HSP90iFGFR3?AMEK FGFRiPTEN loss, or RB inact10-30P/ABRAFi everolimuBRAFi PI3KiERB2, ERB3?A/PBRAFi Lapa ¿?MED12?Mediator ABRAFi TGFBi (YR-290)BCL2A1-MITF?A(PR to ERKi, BRAFi, MEKi; S BRAFi bcla2i, obatoclax
LGX818, MEK162, BKM120, BGJ398, INC280, LEE011 (LOGIC 2)Part IGroup ABRAF andMEK naiveBiopsyGroup BLGX818/MEK162combinationBiopsyat PDAny BRAF/MEKcombination orsingle agents*Biopsyat PDGroup syat PDGen. Ass. and/or Run-inOptionalLGX818/MEK162combination)Part IIBKM120 , BGJ398, INC280 or LEE011 ***LGX818MEK162Genetic Assessment(Biopsy Analysis)Run-in**LGX818/MEK162(first scan after3 weeks)BKM120 , BGJ398, INC280 or LEE011 ***LGX818MEK162Genetic Assessment(Biopsy Analysis)OptionalLGX818/MEK162combinationGenetic Assessment(Biopsy Analysis)BKM120 , BGJ398, INC280 or LEE011 ***LGX818MEK162
Heterogenity intratumoral/intrapatientShi H et al. Cancer Discovery 2014; Wilmott 2012; VanAllen 2014; Romano 2014; Turajlic 2014
BRAF/MEK acquired resistance: how to overcome it?3.1. Identification of the most relevant mechanism of resistance: cfDNA analysis3.2. Triple combinations in first line setting: trying to improve PFS3.3. Deloyed adaptative resistance: on/of Schedule, other combinations?3.4. Using at progression drugs with a broader spectrum of inhibition
3.1 cfDNA as a tool for selecting the targeted drug% alelo mutado10080%5010,48%0%011-12-2014BRAFi MEKiGonzalez-Cao 20159-01-20150,50%13-09-2015 23-11-2015
ctDNA can be used to monitor patient responseMaria Romina Girotti et al. Cancer Discov 2016;6:286
cfDNA next-generation sequencing in MOSCATO trialJovelet. Clin Cancer Res 2016
Slide 15Presented By Keith Flaherty at 2016 ASCO Annual Meeting
NRAS treatment:PD-0332991(CDk4/6i) GSK 1120212(MEKi)CR in 33% of miceKwong. Nature 20121.Can Discovery 20132.Nature 20123.Cell 20134.PNAS 20135.Mol Cancer T 20126. ASCO 2012Huang1Simvast Falvop/MEKiKwong2MEKi CDK4iCorcoran3MEKi abt-263 (bcl-xli)Posch4MEKi PI3KiGreger5MEKi BRAFi PI3KiMeans-Powell6 METi SorafenibNazarian. Nature 2010; McCarthur 2011; Ribas, JCO 2013; Van Allen, 2014
A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patientswith NRAS-mutant melanomaCDK4/6i (LEE011) MEKi (MEK162)OR 82% (N 22)Sosman. ASCO 2014, abs 9009
CHK1 inhibitors in RAS mutant cell linesMorales D, Rosell R et al. ASCO 2016
Clinical 219)CDK4/6singleOngoingPhase ed 2011NCT01390818BKM120PI3KiBRAFiUnknown 2013NCT01512251
Splicing forms p61BRAFV600 6/19 patients: 61kd variant form of BRAF(V600E) that lacks exons 4-8, aregion It could be sensible to higher dose or combination, unless it is alsoobserved in pts with combined treatment (Hartsoughet al , 2014)Poulikakos P. Nature 2011
Whole exome sequencing identified B-RAFV600Eamplification4/20 patientsIn vitro testing: growth inhibition could be achieved with higher dose of BRAFiShi. Nature 2012, Thakur 2013
MEK1/2 mutations MEK1P124 mutations co-occur at low frequency ( 7%)with BRAFV600 mutations. Pre therapy MEK1 codon124 6/87; OR 2/6 (Sosman 2012) MEK1Q56P (1 pts to BRAFi)(Trunzer, 2013). MEK1P162S (1/5 pts): no gives resistanceVan Allen et al. Cancer Discovery 2014 MEK1 mutation at progression 3/20 cases:sensituve t combination MEK2 Q60P (1/5 pts): resit combinationbut sensible to ERKi (Wagle, 2014) MEK2 C125S (R to BRAFi and MEki); MEK2 V35M and L46F and N126D(also resistance to BRAFi or MEKi, but no sointense as C125S (Van Allen 2014)Wagle N et al. Cancer Discovery 2014
AKT1 mut (Q79K)Acquired resistance to BRAFi in PTEN wild typeAdaptative resistance: early rebound of AKTpathway in wild PTEN null or PTEN wild butAKT mutantEarly rebounf of PDGFRB (not EGFR) anddownregulation of MYC (adaptative AKT signalling)In melanomas without early adaptative AKTupregulation is more frequent late resistanceby AKT than in melanomas with early AKT reboundShi H, Ribas et al C Diiscovery 2014:4: 69
SOX10 TGFB signaling increases EGFR and PDGFRB expression9Chong Sun, Liqin Wang et Sidong Huang et al Nature. 2014
IGF-1R, EGFR, erb2, erb3, PDGFVillanueva. Cancer Cell 2010Gopal, CR 2010
3.3. BRAF/MEK adaptative resistance:on/off scheduleBack up informationChong Sun, Liqin Wang et Sidong Huang et al Nature. 2014
Discontinuous dosing strategy attenuates continued dependency on BRAF (V600E)-MEK-ERKsignaling in resistant tumors , akin to reintroducing EGFR TKIs in EGFR mutant NSCLCsfollowing chemotherapy (Sequist et al. Science Trans Med 2011) (Chmielecki 2011)Das Thakur et al. Nature 2013
Intermittent Vemurafenib (iBRAF) Cobimetinib (iMEK):GEM-01-15GEM: Grupo Español de MelanomaCONTINUO (n 58)Melanoma avanzadoBRAFV600 mutado(n 116)ECOG PS 0–1No tto previo 18 yearsAdecuadas funcionesorgánicasV C4semV C4semV C4semV C4semV C4semV C4semV C4semV C4semV C4semOFF2sV C4semV C4sem4semOFF2sINTERMITENTE (n 58)Objetivo principal: SLPObjetivos secundarios Tasa de respuesta SLP 1 año, SLP 2 años SG, SG 1 año, SG 2 años Seguridad cfDNA BRAF V600 subestudio biomarcadoresVemurafenib (960mg BID oral 1-28d) (ROCHE)Cobimetinib (60mg QD oral 1-21d) (ROCHE)Justificación Optimizar esquema de tratamiento V-C Retrasar resistencias Reducir perfil de seguridad Reducir coste imiento
Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is aPost-Translational Mechanism of Kinase Inhibitor Resistance Miles A. Miller et al. Cancer Discov 2016;6:382-399
Gonzalez Cao M et al. ATM 2015
Conclusions Resistance to BRAF inhibitors is mediated by differentmechanisms.– Secondary NRAS mutations– Upregulation of RTKs (PDGFRβ, IGF1R, AXL)– BRAF truncations or amplification Adaptative resistance– On-off scheudle Heterogeneous– Target key signaling node: ERKi, pan RAFi– Methods for looking at the most prevalent resistantmechanism: cfDNA
BRAF and MEK naive LGX818/MEK162 combination Optional LGX818/MEK162 combination) Biopsy Any BRAF/MEK Run-in ** LGX818/MEK162 Part I Group A Group B Genetic Assessment (Biopsy Analysis) Biopsy atPD Gen. Ass. and/or Run-in BKM120 , BGJ398, INC280 or LEE011 *** combination or single agents * (first scan after 3 weeks) Genetic Assessment (Biopsy .
8 MAE 342 –Dynamics of Machines 15 Torfason’s Classification of Mechanisms Snap-Action Mechanisms Linear Actuators Fine Adjustments Clamping Mechanisms Locational Devices Ratchets and Escapements Indexing Mechanisms Swinging or Rocking Mechanisms Reciprocating Mechanisms Reversing Mec
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A commitment to always closing the feedback loop. Summary boxes: beneficiary feedback mechanisms Below are three boxes that summarise key information about drivers for developing feedback mechanisms, examples of mechanisms, and factors affecting how far these mechanisms ar
UNIT 1 SIMPLE MECHANISMS Simple Mechanisms Structure 1.1 Introduction Objectives 1.2 Kinematics of Machines 1.3 Kinematic Link or an Element 1.4 Classification of Links 1.5 Degree of Freedom 1.6 Kinematic Pairs 1.7 Different Pairs 1.7.1 Types of Lower Pair 1.7.2 Higher Pair 1.7.3 Wrapping Pair 1.8 Kinematic Chains
MPLS PW OAM mechanisms are described next, and a brief look at existing layer 2 OAM mechanisms is provided. The article goes on to describe the relationship between end-to-end fault detection and the segment-based OAM mechanisms. MPLS PW An MPLS PW is the mechanism used to carry layer 2 traffic over MPLS. It is a point-to-point
DYNAMIC MODELS WITH THOSE OF REAL MECHANISMS, AND RULES OF DESIGN 151 8.1. Introduction 151 8.2. Comparison of the responses of the various dynamic models of cam mechanisms with those of real mechanisms 151 8.2.1. Four-degrees-of-freedom model 151 8.2.2. Damping 156 8.2.3. Follower
Con: Geneva mechanisms usually require the use of gear reduction. Con: due to the reduction and the use of a cam, Geneva mechanisms have more moving parts than a worm drive Pro: Geneva wheels are less expansive to fabricate than worm drives Con: Geneva mechanisms are limited in the number of discrete positions.
Biologic drugs, as Infliximab (IFX), are widely used in inflammatory bowel disease (IBD). IFX is a chimeric monoclonal immunoglobulin directed against TNF-α and acting in IBD through several mechanisms of action. We divide these mechanisms into central and peripheral. Central mechanisms are considered effective at systemic level, like the
